Selection, synthesis, and anti-inflammatory evaluation of the arylidene malonate derivatives as TLR4 signaling inhibitors.
Selection, synthesis, and anti-inflammatory evaluation of the arylidene malonate derivatives as TLR4 signaling inhibitors.
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DOI：
10.1016/j.bmc.2012.08.022
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发表时间：
2012-10-15
影响因子：
3.5
通讯作者：
Yin H
中科院分区：
文献类型：
--
作者：
Zhang S;Cheng K;Wang X;Yin H
抑制TLR4信号转导是干预多种炎症性疾病病因的重要治疗策略。近年来，有大量的研究旨在探索这一策略，并确定TLR4途径的小分子抑制剂。然而，最近针对TLR4信号通路的一些先进候选药物(如TAK242和厄立特里亚)的失败促使我们继续寻找新的化学支架来抑制这一关键的炎症反应途径。在这里，我们报告了一组新的TLR4信号抑制剂的鉴定，通过基于细胞的筛选。合成了一系列丙二酸芳叉酯类似物，并在小鼠巨噬细胞中测定了它们对脂多糖诱导的一氧化氮(NO)产生的抑制活性。先导化合物1(NCI126224)在纳摩尔-低微摩尔范围内抑制内毒素诱导的核因子-κ-B、肿瘤坏死因子-α、白介素1β(IL-1β)和一氧化氮(NO)的产生。综上所述，这项研究表明1是一种有前途的治疗各种炎症性疾病的候选药物。
Inhibition of TLR4 signaling is an important therapeutic strategy for intervention in the etiology of several pro-inflammatory diseases. There has been intensive research in recent years aiming to explore this strategy, and identify small molecule inhibitors of the TLR4 pathway. However, the recent failure of a number of advanced drug candidates targeting TLR4 signaling (e.g. TAK242 and Eritoran) prompted us to continue the search for novel chemical scaffolds to inhibit this critical inflammatory response pathway. Here we report the identification of a group of new TLR4 signaling inhibitors through a cell-based screening. A series of arylidene malonate analogs were synthesized and assayed in murine macrophages for their inhibitory activity against LPS-induced nitric oxide (NO) production. The lead compound 1 (NCI126224) was found to suppress LPS-induced production of nuclear factor-kappaB (NF-κB), tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and nitric oxide (NO) in the nanomolar-low micromolar range. Taken together, this study demonstrates that 1 is a promising potential therapeutic candidate for various inflammatory diseases.
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DOI：
10.3390/molecules14104166
发表时间：
2009-10-19
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Chang S;Yin SL;Wang J;Jing YK;Dong JH
通讯作者：
Dong JH
影响因子：
8.8
作者：
Rice, Todd W.;Wheeler, Arthur P.;Cohen, Jon
通讯作者：
Cohen, Jon
影响因子：
64.8
作者：
Park, Beom Seok;Song, Dong Hyun;Lee, Jie-Oh
通讯作者：
Lee, Jie-Oh
影响因子：
3.5
作者：
Adediran, S. A.;Cabaret, D.;Lohier, J. -F.;Wakselman, M.;Pratt, R. F.
通讯作者：
Pratt, R. F.
影响因子：
4.4
作者：
Hawiger, J
通讯作者：
Hawiger, J